Nowhere has drug-resistant TB generated more alarm than in South Africa, where synergies between endemic TB and HIV have caused 'explosive' increases in TB incidence and case- fatality rates. The most resistant form of TB, extensively drug resistant tuberculosis (XDR-TB), is increasingly prevalent in South Africa. An important obstacle to improving survival for XDR-TB is the lack of a rapid, biomarker that serves to identify viable Mtb, allow drug susceptibility testing in clinical sputum samples and detect Mtb persisters. Utilizing two novel recombinant reporter mycobacteriophages, we have developed assays with superior test characteristics that will allow us to characterize complex drug resistance and mycobacterial persistence in vivo to improve treatment outcomes for drug-resistant TB/HIV patients. This proposal is a result of an ongoing funded collaboration between researchers at Albert Einstein College of Medicine, the KwaZulu-Natal Research Institute for Research in Tuberculosis and HIV/AIDS (K-RITH), and the Sanger Institute. This is an innovative approach with the potential to make a substantial impact in our ability to comprehensively diagnose drug-resistant tuberculosis and characterize Mtb persister populations thereby improving treatment outcomes, reducing transmission and preventing amplification of drug resistance on treatment.